Journal Article

Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations

Kim, Kevin B, Puzanov, Igor, Kefford, Richard F, Singh, Ajay, Hamid, Omid, Flaherty, Keith T, Schuchter, Lynn, Gonzalez, Rene, Cebon, Jonathan, Burris, Howard A, Ouellet, Daniele, Little, Shonda, Long, Georgina V, Weber, Jeffrey, Algazi, Alain, Sun, Peng, Lebowitz, Peter, Ibrahim, Nageatte, Patel, Kiran, Infante, Jeffery R, Sosman, Jeffrey, Kudchadkar, Ragini, Daud, Adil, Lewis, Karl, Falchook, Gerald, Allred, Alicia

2012

Overview

The combination of a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in patients with metastatic melanoma produced a significantly higher response rate than dabrafenib alone. Median progression-free survival was 9.4 months, as compared with 5.8 months with dabrafenib alone. Pharmacologic inhibition of the mitogen-activated protein kinase (MAPK) pathway has proved to be a major advance in the treatment of metastatic melanoma. The use of vemurafenib and dabrafenib, agents that block MAPK signaling in patients with melanoma and the BRAF V600E mutation, has been associated with prolonged survival and progression-free survival, respectively, in randomized phase 3 trials involving patients with previously untreated melanoma. 1 – 6 Trametinib mediates blockade of MAPK kinase (MEK), which is downstream of BRAF in the MAPK pathway and has been associated with improved progression-free and overall survival in BRAF V600 melanoma (comprising both V600E and V600K mutations). . . .

• Publisher: Massachusetts Medical Society
• Subject: Adult / Aged / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Biological and medical sciences / Cell survival / Dermatology / Disease-Free Survival / Drug dosages / Drug Therapy, Combination - adverse effects / Female / Fever / Fever - chemically induced / General aspects / Humans / Imidazoles - adverse effects / Imidazoles - pharmacokinetics / Imidazoles - therapeutic use / Kinases / Male / MAP kinase / MAP Kinase Signaling System - drug effects / Medical sciences / Melanoma / Melanoma - drug therapy / Melanoma - genetics / Melanoma - secondary / Metastases / Middle Aged / Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors / Mutation / Oximes - adverse effects / Oximes - pharmacokinetics / Oximes - therapeutic use / Patients / Protein kinase / Proto-Oncogene Proteins B-raf - antagonists & inhibitors / Proto-Oncogene Proteins B-raf - genetics / Pyridones - adverse effects / Pyridones - pharmacokinetics / Pyridones - therapeutic use / Pyrimidinones - adverse effects / Pyrimidinones - pharmacokinetics / Pyrimidinones - therapeutic use / Skin diseases / Squamous cell carcinoma / Tumors of the skin and soft tissue. Premalignant lesions